Aristolochic acid I induces impairment in spermatogonial stem cell in rodents

2021 ◽  
Author(s):  
Yongzhen Liu ◽  
Xiang He ◽  
Yuli Wang ◽  
Houzu Zhou ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adult Stem Cells ◽  
Aristolochic Acid ◽  
Adult Life ◽  
Proliferation Index ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Early Stages ◽  
Testicular Impairment ◽  
Aristolochic Acid I

Abstract Aristolochic acid I (AAI) is a natural bioactive substance found in plants from the Aristolochiaceae family and impairs spermatogenesis. However, whether AAI-induced spermatogenesis impairment starts at the early stages of spermatogenesis has not yet been determined. Spermatogonial stem cells (SSCs) are undifferentiated spermatogonia that balance self-renewing and differentiating divisions to maintain spermatogenesis throughout adult life and are the only adult stem cells capable of passing genes onto the next generation. The objective of this study was to investigate whether AAI impairs SSCs during the early stages of spermatogenesis. After AAI treatment, we observed looser, smaller and fewer colonies, decreased cell viability, a decreased relative cell proliferation index, and increased apoptosis in SSCs in a concentration- and/or time-dependent manner. Additionally, AAI promoted apoptosis in SSCs, which was accompanied by upregulation of caspase 3, P53 and BAX expression and downregulation of Bcl-2 expression, and suppressed autophagy, which was accompanied by upregulation of P62 expression and downregulation of ATG5 and LC3B expression, in a concentration-dependent manner. Then we found that AAI impaired spermatogenesis in rats, as identified by degeneration of the seminiferous epithelium, and increased apoptosis of testicular cells. Taken together, our findings demonstrate that AAI causes damage to SSCs and implicate apoptosis and autophagy in this process. The impairment of SSCs may contribute to AAI-induced testicular impairment. Our findings provide crucial information for the human application of botanical products containing trace amounts of AAI.

scholarly journals Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Yan Xu ◽  
Huan Yuan ◽  
Yi Luo ◽  
Yu-Jie Zhao ◽  
Jian-Hui Xiao
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Signaling Pathway ◽  
Adult Stem Cells ◽  
Telomerase Activity ◽  
Related Factor ◽  
Dependent Manner ◽  
Ganoderic Acid ◽  
Nrf2 Signaling Pathway

Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established in vitro using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from Ganoderma lucidum, on hAMSC senescence. GA-D significantly inhibited β-galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 μM to 10 μM, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and β-galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.

Effects of plant lectin and extracts on adhesion molecules of endothelial progenitors

2011 ◽  
Vol 6 (3) ◽  
pp. 330-341 ◽  
Author(s):  
Florin Iordache ◽  
Iordache Carmen ◽  
Pop Aneta ◽  
Marilena Lupu ◽  
Eugen Andrei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adhesion Molecules ◽  
Adult Stem Cells ◽  
Mononuclear Cells ◽  
Vascular Tissue ◽  
Dependent Manner ◽  
Wound Healing Assay ◽  
Rt Pcr ◽  
Calendula Officinalis ◽  
Concentration Dependent Manner

AbstractPromise of cell therapy has advanced the use of adult stem cells towards the development of novel approaches to promote regeneration of injured endothelium. The aim of this study was to stimulate endothelial progenitor cells (EPCs) with lectin isolated from Solanum tuberosum (potato) shoot and Calendula officinalis (marigold) extracts, in order to increase EPCs proliferation and gene expression of molecules with roles in chemotaxis and adhesion for a better attachment to injured vascular tissue. EPCs were differentiated from umbilical cord blood-derived mononuclear cells and characterized by light microscopy, flow cytometry, and vascular tube-like structures formation on Matrigel. Cell proliferation was determined by MTS assay, and gene expression of molecules involved in EPCs adhesion (VCAM-1, VE-cadherin, ICAM-1, PECAM-1, P-selectin) and chemotaxis was determined (CXCR4, Tie-2) by RT-PCR. For the assessment of cell motility, wound-healing assay was employed. Both potato shoot lectin and marigold extracts stimulated EPCs proliferation in a concentration dependent manner and were able to increase expression of adhesion and chemotactic molecules. Marigold flower extract proved to be more efficient. This study demonstrates the usefulness of potato lectin and marigold extracts to increase EPCs proliferation and modulate gene expression of chemotactic and adhesion molecules, which may facilitate EPCs attachment to injured endothelium.

scholarly journals Hypermethylation in Calca Promoter Inhibited ASC Osteogenic Differentiation in Rats with Type 2 Diabetic Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Lei Wang ◽  
Feng Ding ◽  
Shaojie Shi ◽  
Xingxing Wang ◽  
Sijia Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Stem Cells ◽  
Osteogenic Differentiation ◽  
Methylation Level ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Target Fragment

The abnormal environment of type 2 diabetes mellitus (T2DM) leads to a substantial decrease in osteogenic function of stem cells. However, the gene sequence does not vary before and after disease for the patient. This phenomenon may be related to changes in osteogenesis-related gene expression caused by DNA methylation. In this study, we established T2DM models to extract adipose-derived stem cells (ASCs) for different gene identifications through DNA methylation sequencing. Specific fragments of methylation changes in the target gene (Calca) were identified by IGV analysis. CGRP was applied to compare the effects on ASCs-T2DM morphology via phalloidin staining, proliferation through CCK-8 assay, and osteogenic differentiation with osteogenic staining, qPCR, and repair of calvarial defect. Furthermore, 5-azacytidine (5-az) was used to intervene ASCs-T2DM to verify the relationship between the methylation level of the target fragment and expression of Calca. We found that the DNA methylation level of target fragment of Calca in ASCs-T2DM was higher than that in ASCs-C. CGRP intervention showed that it did not change the morphology of ASCs-T2DM but could improve proliferation within a certain range. Meanwhile, it could significantly enhance the formation of ALP and calcium nodules in ASCs-T2DM, increase the expression of osteogenesis-related genes in vitro, and promote the healing of calvarial defects of T2DM rat in a concentration-dependent manner. 5-az intervention indicated that the reduction of the methylation level in Calca target fragment of ASCs-T2DM indeed escalated the gene expression, which may be related to DNMT1. Taken together, the environment of T2DM could upregulate the methylation level in the promoter region of Calca and then decrease the Calca expression. The coding product of Calca revealed a promoting role for osteogenic differentiation of ASCs-T2DM. This result provides an implication for us to understand the mechanism of the decreased osteogenic ability of ASCs-T2DM and improve its osteogenic capacity.

From Embryo to Adult: One Carbon Metabolism in Stem Cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Özlem Altundag ◽  
Betül Çelebi-Saltik
Keyword(s):  
Stem Cells ◽  
Embryonic Development ◽  
Adult Stem Cells ◽  
Adult Life ◽  
Dietary Factors ◽  
Metabolic Reprogramming ◽  
Premature Delivery ◽  
Differentiation Potential ◽  
Tissue Cells ◽  
C Metabolism

: Stem cells are undifferentiated cells with self-renewal property with varying differentiation potential that allow the regeneration of tissue cells of an organism throughout adult life beginning with embryonic development. Through the asymmetric cell divisions, each stem cell replicates itself and produces an offspring identical with the mother cell, and a daughter cell that posses the characteristics of a progenitor cell and commits to a specific lineage to differentiate into tissue cells to maintain homeostasis. To maintain a pool of stem cells to ensure tissue regeneration and homeostasis, it is important to regulate the metabolic functioning of stem cells, progenitor cells and adult tissue stem cells that will meet their internal and external needs. Upon fertilization, the zygote transforms metabolic reprogramming while implantation, embryonic development, organogenesis processes and after birth through adult life. Metabolism in stem cells is a concept that is relatively new to be enlightened. There are no adequate and comprehensives in vitro studies on the comparative analysis of the effects of one-carbon (1-C) metabolism on fetal and adult stem cells compared to embryonic and cancer stem cells’ studies that have been reported recently Since 1-C metabolism is linking parental environmental/dietary factors and fetal development, investigating the epigenetic, genetic, metabolic and developmental effects on adult period is necessary. Several mutations and abnormalities in 1-C metabolism noted in disease changing from diabetes, cancer, pregnancyrelated outcomes such as pre-eclampsia, spontaneous abortion, placental abruption, premature delivery, cardiovascular diseases. In this review, the effects of 1-C metabolism, mainly the methionine and folate metabolism, in stem cells that exist in different developmental stages will be discussed.

STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi24
Author(s):  
Kelly Mitchell ◽  
Joseph Alvarado ◽  
Christopher Goins ◽  
Steven Martinez ◽  
Jonathan Macdonald ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Self Renewal ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

scholarly journals AMPK Activation Mediated by Hinokitiol Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells through Autophagy Flux

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Ju-Hee Lee ◽  
Jae-Kyo Jeong ◽  
Sang-Youel Park
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Experimental Approach ◽  
Adipogenic Differentiation ◽  
Dependent Manner ◽  
Ampk Activation ◽  
Autophagy Flux ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Ampk Phosphorylation

Background and Purpose. Hinokitiol, a natural monopenoid present in the essential oil of Calocedrus formosana heartwood, exerts potent anticancer, anti-inflammatory, antibacterial, and neuroprotective effects on various cells. However, the antiobesity effect of hinokitiol on adipocytes is unclear. Experimental Approach. In this study, we observed that hinokitiol affected the differentiation to adipocytes in mesenchymal stem cells (MSCs). Hinokitiol was treated with 3-isobutyl-1-methylxanthine, insulin, and dexamethasone to induce differentiation and maturing adipocytes in cultured MSCs. Key Results. Hinokitiol treatment of MSCs decreased their differentiation to mature adipocytes and increased AMPK phosphorylation in a concentration-dependent manner. Moreover, we confirmed that the antiadipogenic effect of hinokitiol was associated with autophagy. The levels of LC3-II decreased and those of p62 increased in hinokitiol-treated MSCs. The treatment of hinokitiol-treated MSCs with the autophagy activator, rapamycin, restored the hinokitiol-induced decrease in the adipocyte differentiation of MSCs. The inhibition of AMPK phosphorylation also suppressed hinokitiol-mediated inhibition of autophagy and antiadipogenic effects. Conclusions and Implications. Taken together, these results indicated that AMPK activation and autophagy flux inhibition mediated by hinokitiol inhibited lipid accumulation and differentiation of MSCs to adipocytes and also suggest that differentiation of mesenchymal stem cells may be regulated by using the modulator of autophagy flux and AMPK signals including hinokitiol.

scholarly journals Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure

Oncotarget ◽  
2016 ◽  
Vol 7 (48) ◽  
pp. 78872-78882 ◽  
Author(s):  
Tong Li ◽  
Ke Jin ◽  
Dan-yan Zhu ◽  
Lu Li ◽  
Zheng-rong Mao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Aristolochic Acid ◽  
Embryonic Stem ◽  
Aristolochic Acid I

scholarly journals Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells

2019 ◽  
Vol 20 (5) ◽  
pp. 1027 ◽  
Author(s):  
Bijaya Upadhyaya ◽  
Yi Liu ◽  
Moul Dey
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Transcription Factor ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Dependent Manner ◽  
Phenethyl Isothiocyanate ◽  
Concentration Dependent Manner

Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDHhi CSCs from HeLa parental cells (p < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDHhi hCSCs in a concentration-dependent manner (p < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs (p ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, p < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs.

Effects of inhibitors of arachidonic acid turnover on the production of prostaglandins by the guinea-pig uterus

Reproduction ◽  
2000 ◽  
pp. 181-186 ◽  
Author(s):  
SJ Norman ◽  
NL Poyser
Keyword(s):  
Arachidonic Acid ◽  
Guinea Pig ◽  
Aristolochic Acid ◽  
Acid Uptake ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Rate Limiting Step ◽  
Free Arachidonic Acid ◽  
Rate Limiting

The supply of free arachidonic acid from phospholipids is generally regarded as the rate-limiting step for prostaglandin (PG) synthesis by tissues. Two enzymes involved in arachidonic acid uptake into, and release from, phospholipids are acyl-CoA:lysophospholipid acyltransferase (ACLAT) and phospholipase A2 (PLA2), respectively. PGF2 alpha produced by the endometrium induces luteolysis in several species including guinea-pigs. Thimerosal, an inhibitor of ACLAT, and aristolochic acid, an inhibitor of PLA2, both reduced, in a concentration-dependent manner, the output of PGF2 alpha from guinea-pig endometrium cultured for 24 h on days 7 and 15 of the oestrous cycle. This study showed that the continual production of PGF 2 alpha by guinea-pig endometrium is not only dependent upon the activity of PLA2 for releasing free arachidonic acid for PGF2 alpha synthesis, but also on the incorporation of arachidonic acid into the phospholipid pool by the activity of ACLAT. The inhibitory effects of thimerosal and aristolochic acid on the outputs of PGE2 and 6-keto-PGF1 alpha were less marked, particularly on day 7 when the low output of PGE2 was unaffected and the output of 6-keto-PGF1 alpha was increased at the lower concentrations of thimerosal. This finding indicates that there are different pools of arachidonic acid bound as phospholipid for the syntheses of PGF2 alpha and 6-keto-PGF1 alpha by guinea-pig endometrium.

scholarly journals Chemical Activation of the Hypoxia-Inducible Factor Reversibly Reduces Tendon Stem Cell Proliferation, Inhibits Their Differentiation, and Maintains Cell Undifferentiation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Alessandra Menon ◽  
Pasquale Creo ◽  
Marco Piccoli ◽  
Sonia Bergante ◽  
Erika Conforti ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cell Response ◽  
Adult Stem Cells ◽  
Chemical Activation ◽  
Hypoxia Inducible Factor ◽  
Adult Stem Cell ◽  
Dependent Manner

Adult stem cell-based therapeutic approaches for tissue regeneration have been proposed for several years. However, adult stem cells are usually limited in number and difficult to be expanded in vitro, and they usually tend to quickly lose their potency with passages, as they differentiate and become senescent. Culturing stem cells under reduced oxygen tensions (below 21%) has been proposed as a tool to increase cell proliferation, but many studies reported opposite effects. In particular, cell response to hypoxia seems to be very stem cell type specific. Nonetheless, it is clear that a major role in this process is played by the hypoxia inducible factor (HIF), the master regulator of cell response to oxygen deprivation, which affects cell metabolism and differentiation. Herein, we report that a chemical activation of HIF in human tendon stem cells reduces their proliferation and inhibits their differentiation in a reversible and dose-dependent manner. These results support the notion that hypoxia, by activating HIF, plays a crucial role in preserving stem cells in an undifferentiated state in the “hypoxic niches” present in the tissue in which they reside before migrating in more oxygenated areas to heal a damaged tissue.

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